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"In addition, from a methodologic perspective, Rheb CA expression rapidly (6-8 hours) activates the mTOR pathway as compared to other experimental strategies such as conditional transgenic mice, small hairpin RNA (shRNA), or CRISPR and Cas9 vectors because the timing of mTORC1 activation depends on the half-life of the KD/KO protein of interest."

"Indeed, we have shown, as a proof of principle, that knocking down TSC2 or overexpressing RHEB enhances mTOR activity in KO cells."

"Rheb activation of mTOR is more dependent on farnesylation than on postprenylation CAAX processing."

"This explains why overexpressed Rheb activates mTOR in the absence of amino acids; presumably the Rheb-mTOR interaction is driven by mass action in this case, and no longer requires the amino acid stimulated movement of mTOR to late endosomes."

"Rheb has been shown to exclusively activate the mTOR pathway without affecting other signaling pathways."

"Akt mediated phosphorylation can downregulate tuberin 's GTPase activating potential toward Rheb, which modulates mTOR complex 1 through FKBP38 by directly binding to mTOR [XREF_BIBR]."

"Full-length TSC2 protein interacts with TSC1 to inhibit the activation of mTOR by Rheb."

"When free of TSC1/2, RHEB activates mTOR within a rapamycin sensitive protein complex called mTORC1."

"Previous studies have shown that the small GTPase Rheb increases mTOR activity by sequestering the mTOR inhibitor FKBP-38 (Bai et al., 2007; Codeluppi et al., 2009)."

"Amino acids on the other hand signal to mTORC1 through the Rag family of GTPases, by mediating the activation of mTOR by RHEB at the lysosome [XREF_BIBR, XREF_BIBR]."

"Akt then phosphorylates several substrates, one of which is the tuberous sclerosis complex (TSC1/2), a GTPase activating protein complex that suppresses Rheb, a GTPase that contributes directly to the activation of mTOR"

"Hypoxia results in energy starvation and activation of the AMPK/TSC2/Rheb/mTOR pathway"

"Class I PI3K, a heterodimer consisting of a regulatory and a catalytic subunit, is a negative regulator of autophagy that is activated by the insulin receptor and the insulin receptor substrate proteins. Activated class I PI3K mainly uses PtdIns(4,5)P2 as substrate to yield PtdIns(3,4,5)P3 at the plasma membrane, which increases membrane recruitment of both PKB/Akt and its activator phosphoinositide- dependent protein kinase 1, leading to the activation of PKB/Akt, a downstream negative regulator of autophagy. Activated PKB/Akt further activates mTOR through inhibiting a downstream protein complex, the tuberous sclerosis complex 1/2, that represses the small G protein Rheb, causing inhibition of autophagy."

"Akt then phosphorylates several substrates, one of which is the tuberous sclerosis complex (TSC1/2), a GTPase activating protein complex that suppresses Rheb, a GTPase that contributes directly to the activation of mTOR"

"The TOR complex 1 is a direct target of Rheb-GTP, whose binding enables activation of the TOR kinase"

"Although the mechanism through which the TSC1-TSC2 complex represses mTOR signalling is incompletely defined, recent studies (Garami et al. 2003; Zhang et al. 2003) have suggested that, in part, TSC2 may act through the small GTPase ras homologue enriched in brain (Rheb) in regulating mTOR. Here, TSC2 is a GTPase-activating protein for Rheb that normally represses Rheb function (Garami et al. 2003; Zhang et al. 2003). How Rheb modulates mTOR-dependent signalling is unknown."

"Tuberous sclerosis complex protein 2 is a GTPase activator protein for Rheb that is inhibited by amino acids, allowing Rheb to activate mTOR through a mechanism still to be delineated."

"Rheb-GTP then activates mammalian (m)TOR, either directly or indirectly, through an unknown effector (question mark)."

"Genetic support for a linear Akt1-mTOR-p70S6K pathway has recently come from reports demonstrating that the tuberous sclerosis complex 1 and 2 proteins (Tsc1 and Tsc2) can inhibit mTOR (Fig. 1). Akt1 phosphorylates Tsc2, thereby activating mTOR at least in part by disrupting the Tsc1-Tsc2 complex [54]."

"Genetic support for a linear Akt1-mTOR-p70S6K pathway has recently come from reports demonstrating that the tuberous sclerosis complex 1 and 2 proteins (Tsc1 and Tsc2) can inhibit mTOR (Fig. 1). Akt1 phosphorylates Tsc2, thereby activating mTOR at least in part by disrupting the Tsc1-Tsc2 complex [54]."

"The main conclusion of our study is that RGS10 suppression causes an increase in activated, GTP bound Rheb and results in mTOR pathway activation among ovarian cancer cells."

"Rheb when associated with GTP stimulates mTOR activity [XREF_BIBR]."

"PI3K and Akt signaling suppresses the activity of the Rheb GTPase activating complex (TSC1 and TSC2) and thereby increases the level of GTP bound Rheb, which in turn induces mTOR signaling [XREF_BIBR]."

"GTP bound Rheb activates the mTOR kinase activity."

"Therefore, the sequestration of TSC2 with 14-3-3 increases the relative amount of GTP bound Rheb and this activates mTOR in muscle cells XREF_BIBR."

"Moreover, activation of Akt has been reported to inactivate the TSC1/2 complex, leading to increased active GTP bound Rheb, which activates mTOR XREF_BIBR."

"In this case, GTP bound RHEB activates mTOR."

"To further determine whetherENDOG mediated autophagy promotion is mTOR dependent, we used a constitutively active form of RHEB (RHEB Q64L) to continuously activate mTOR 19."

"As a result, compared to the empty vector controls, RHEB Q64L partially restored mTOR activity, as shown by the increased phosphorylation of ULK1 and 4EBP1."

"Given the fact that ENDOG induced autophagy has only been partially restored in the presenceof RHEB Q64L, which continuously activates mTOR, we reasoned that an additional pathway might exist in ENDOG promoted autophagy."

"Rheb interacts directly with mTOR and activates mTOR kinase, whereas Rabin8 interacts with Rheb and inhibits the phosphorylation of Ser235 and Ser236 in small ribosomal subunit protein S6."

"There is some evidence indicating that Rheb, a small guanosine triphosphate (GTP)-binding protein, interacts with mTOR and activates the enzymatic activity of mTOR by binding the Rheb-GTP to mTOR directly."

"Expression of a constitutively active Rheb enhanced mTOR activity and increased the fiber size in VCP-IBM mouse skeletal muscle."

"To examine the role of mTOR in metformin 's action on tau phosphorylation, we inhibited its activity with rapamycin, or activated it by overexpressing a constitutive active mutant of the mTOR activator Rheb (S16H-Rheb) [XREF_BIBR]."

"In this model, GTP bound Rheb binds to FKBP38 and induces the release and activation of mTOR."